The goal of this project is to determine whether deficits in cytosolic free calcium are diagnostic for Alzheimer's disease. Several deficits in calcium homeostasis and calcium dependent processes have been described for peripheral tissues from Alzheimer's patients; these include a deficits in calcium homeostasis, a decline in protein phosphorylation, growth factor response, cell spreading, glucose and glutamine oxidation. The main objective of this proposal is to determine whether the deficits in cytosolic free calcium concentration in cultured skin fibroblasts from Alzheimer's patients differ from that in patients with other dementing illnesses (e.g., Pick's disease, Parkinson's dementia, multi-infarct dementia). The mechanisms for the decline in cytosolic free calcium in Alzheimer's disease are unclear. The calcium binding proteins play a role in buffering intracellular calcium and studies are designed to determine whether they are altered during Alzheimer's disease. Fibroblasts from individuals who are at risk for developing Alzheimer's disease (e.g. familial Alzheimer's disease) will also be tested to determine whether deficits in cytosolic free calcium appear prior to the clinical signs of the disorder. These approaches will help us to diagnose Alzheimer's disease, understand the mechanisms that underlie the degenerative disorder and aid in the design of effective therapeutic strategies.